A.

Hislop ERS course April 07

Asthma in preschool children: where are we at?

Marille Pijnenburg, MD PhD Dept. Paediatric Respiratory Medicine Erasmus MC Sophia Childrens Hospital

Asthma in preschool children

Epidemiology
Why infants wheeze Why we should make a diagnosis

How to make a diagnosis

Treatment Prevention of asthma?

Question
The parents say hes wheezing.
The doctor agrees in:
A
B C D

10%
45% 70% 90%

Wheezing in preschool children: where are we talking about?

Agreement between parents and doctor ca 45%

(Cane et al. Arch Dis Child 2001)

Second-hand information No common language Child often away from parents Underestimation by (smoking!) parents
(Crombie et al. Thorax 2001)

Message
IT IS ESSENTIAL TO SEE WHEEZING CHILDREN YOURSELF AT THE OUTPATIENT CLINIC IN CASE OF TYPICAL COMPLAINTS

Epidemiology
1 out of every 3 children will have at least 1 episode of wheezing before age 3 yrs Not all that wheezes is asthma Children > 5 yrs with asthma:

30% onset of symptoms in first yr of life

70% before age 3 80-90% before age 6

Epidemiology

1980-2000:
- large prospective epidemiological studies (Tucson, Perth, Aberdeen)

- different wheezing phenotypes in preschool children

Question
1,5 year old boy. Third wheezing episode. Recurrent upper airway infections. Response to bronchodilators doubtful. Mother smokes. IgE 10, no specific IgE

This child has: A Early onset asthma

B Transient early wheeze

C Viral induced wheeze D You cant say

Wheezing phenotypes

Martinez et al.

Wheezing phenotypes
Transient early wheezing
Starts in first year of life No family history/ no sensitization

Reduced pulmonary function

Resolves around the age of 3 Other risk factors: prematurity and SGA, sibs,day care, exposure to tobacco smoke, male gender, lower socioeconomic status, lower maternal pulmonary function?

Wheezing phenotypes
Nonatopic (viral) wheezing Intermittent airway obstruction during viral infections Probably no inflammation No atopy Episode-free intervals Normal lung function at birth Spontaneous improvement Risk factors: maternal smoking, SGA, bottle feedings

Wheezing phenotypes
Persistent atopic wheezing Starts after 1st year Early allergic sensitization Positive fam history (OR 4) Eczema (OR 2-3)

Symptoms apart from viral infections

Normal lung function at birth, develop airways obstruction Pos. response to bronchodilators/ ICS More often: first child, no day care attendance, higher socioeconomic status

Epidemiology
High prevalence of preschool wheezing
Not all that wheezes is asthma Clinical applicability of wheezing phenotypes in individuals is limited

Asthma in preschool children

Epidemiology
Why infants wheeze Why we should make a diagnosis

Diagnosis
Treatment Prevention

Why infants wheeze: considerations

Anatomical Physiological Immunological

Why infants wheeze: anatomical considerations

Deficient collateral channels of ventilation
Increased airway smooth muscle, less cartilage Mechanically disadvantaged diaphragm

Why infants wheeze: physiological considerations

Airway caliber
Airway tethering Elastic recoil

Increased nasal resistance

Airway caliber and resistance (Raw= 1/r5)

Diameter

Resistance

5 mm

3 mm

13

Airway caliber and resistance (Raw= 1/r5)

Diameter Resistance

5 mm

Bronchospasm, mucosal oedema, mucus plugging

4 mm

3 mm

13

Airway tethering

Traction exerted on the airway wall by the elastic components of the surrounding alveoli. Infants: less alveolar attachments

Decreased elastic recoil

Compliant chest wall
Tendency to airway closure

Increased nasal resistance

nasal resistance may account for 50% of total airway resistance

Why infants wheeze: immunological considerations

Immaturity of the immune system High load of viral infections (6-8/yr is normal): RSV, adeno, parainfluenza, metapneumo

Why infants wheeze?

Why dont all infants wheeze ? (Janet Stocks 1999)

Asthma in preschool children

Epidemiology
Why infants wheeze Why we should make a diagnosis

Diagnosis
Treatment Prevention

Why diagnose asthma in preschool children?

Manage symptoms and avoid triggers Identify those children who will benefit from treatment Identify most effective treatment Avoid overtreatment Estimate prognosis

Preschool wheezing and atopy

atopic

Prevalence (%)

non-atopic

Illi et al Lancet 2006.

Age (yrs)

no wheeze at school age

non-atopic wheeze

atopic wheeze

FEV1 (%FVC)

FVC (% pred)

FEV1 (% pred)

MEF 75 (%pred)

MEF 50 (%pred)

MEF 25 (%pred)

Why diagnose asthma in preschool children?

Estimate prognosis: Occurrence of wheezing in children 3-4 yrs associated with future asthma and reduced pulmonary function Significant loss of PF seems to occur between age 1 and 6 in persistent wheezers Pulmonary function as a child principal determinant of PF in adulthood Pick up children at risk for progressive disease: better management, reduced morbidity (mortality). Prevent remodeling?

Remodeling and preschool asthma

A: decreased sGAW, reversibilty + B: decreased sGAW, reversibilty C: normal sGAW D: difficult asthma, median 10 yrs E: healthy, median 10 yrs F: healthy adults

n=

16

22

15

17

10

Saglani and Malmstrom et al. AJRCCM 2005

Pathology of asthma in young children

Highly selected group

No appropriate control group Heterogeneity

Limited sample size

Pathology of asthma in young children

n = 47, median age 26 months, severe recurrent wheezing

< 18 mo 18-36 mo >36 mo tot

N= RBM score > 1 Eosinophilia score >0

15 0 5

10 1 4

11 9 7

36 10 16

Saglani et al. Eur Respir J 2006.

Pathology of asthma in young children

Airway remodeling does not seem to start before the age of 3 yrs Eosinophilic inflammation not predominant in young children Lack of biopsy studies; provide essential information

Asthma in preschool children

Epidemiology
Why infants wheeze Why we should make a diagnosis

How to make a diagnosis

Treatment Prevention

Diagnosis
Making a definitive diagnosis in children younger than 3 years of age who experience recurrent respiratory symptoms may be one of the last true art forms in medicine.
Strunk. Pediatrics 2002.

Diagnosis
Is it atypical wheeze? If it is typical wheeze: is it asthma?

Diagnostic tests
Diagnostic approach

Question
For the diagnosis of asthma in a 1,5 year old child I make use of: A B only the history allergy testing

C
D

Chest X-ray
Lung function tests

Atypical wheeze: history

Neonatal onset, neonatal history Sudden onset Frequent productive cough No response to bronchodilators or ICS

Continuous, less symptom free intervals

Negative family history No relation with infections Related to feedings, supine position Systemic infections

Atypical wheeze: physical exam

failure to thrive, abnormal chest, (clubbing) severe lower airways infections located abnormalities at auscultation (monophonic wheeze, asymmetrical breathing sounds) inspiratory stridor

Atypical wheeze: Cost-effective diagnostic tests

CXR Sweattest Allergy skin testing (barium swallow

CT scan thorax)
Positive family history helpful in recognizing asthma in < 50%

Diagnostic tests for preschool asthma

Predictive index asthma

Early frequent wheezer plus at least one of two major criteria or two of three minor criteria.

Major Parental DD asthma DD eczema

Minor DD allergic rhinitis

Wheezing apart from colds

Eosinophils > 4%

Castro-Rodriguez, AJRCCM 2000

Diagnostic tests for preschool asthma

(raised volume) rapid thoracic compression technique Not for routine clinical use

Rint
-Measures airway resistance -Ratio between airflow and mouth pressure during a brief interruption.

Impuls oscillometry
Measures the response of the respiratory system to an externally applied pressure pulse

Exhaled nitric oxide

FENO is elevated in steroid-nave asthmatics Correlates with eosinophilic inflammation Treatment with ICS reduces FENO in a dose-dependent manner

Exhaled nitric oxide in preschool wheeze

p=0.003 p=0.04

Gabriele et al. Pediatr Res 2006

N = 100 53 21 24 20

Question
At my department we can use: A B C Rint and/or IOS Rapid Thoracic Compression FENO measurements

D
E

all of the above

none of the above

Diagnostic tests for preschool wheeze

Useful in epidemiological studies and research
Utility in individuals limited CLINICAL usefulness depends on validity of the test, overlap between healthy and diseased, reproducibility, assessment of response to treatment

Diagnostic approach
Presenting Symptoms

Detailed history (risk factors, triggers) and physical examination Could it be asthma? Probably
Look at: - triggers - complications - co-morbidity Therapeutic plan
Allergy testing

No

Possibly

Alternative management, further investigations/ specialist assistance

Diff. diagnostic tests and/or trials of asthma therapy Asthma likely Asthma unlikely

poor response

good response

Modified from Silverman et al. Wheezing disorders in infants and young children.

Asthma in preschool children

Epidemiology
Why infants wheeze Why we should make a diagnosis

How to make a diagnosis

Treatment Prevention

Treatment

The available literature on treatment of asthma in children 5 years and younger precludes detailed treatment recommendations.
GINA guidelines 2006.

Question
1,5 year old boy. Third wheezing episode. Recurrent upper airway infections.

Response to bronchodilators doubtful.

Mother smokes. IgE 10, no specific IgE Wheezing at phys exam, tachypnoea.

In this child I would: A start (a trial of) ICS plus bronchodilators B give a course of prednisone C wait and see D give bronchodilators on demand

Treatment
Majority of infants: wheezing is transient and benign
Preventive measures: avoid passive smoking, breast feeding Bronchodilators Inhaled corticosteroids

Treatment bronchodilators
...no clear benefit of using B2-agonists in the
management of recurrent wheeze .. conflicting evidence. Cochrane Database Syst Rev. 2002 Effective in subgroups not enough evidence to support the uncritical use of anti-cholinergic therapy for wheezing infants, although parents using it at home were able to identify benefits. Cochrane Database Syst Rev. 2002 Subgroups?

Treatment - ICS
Studies differ in
Different phenotypes Endpoints (symptoms, lung function, FENO)

Age
Type of drug, dosis

Number of patients

RCT on ICS in wheezing < 4 yr

n Age (months) Drug, Daily dose Device wks

Endpoints Symptoms or LF

Effect
Teper 05 Maayan86 Bisgaard90 Noble 92 Connett 93 Kraemer97 Bisgaard99 Teper 04 26 9 77 15 40 29 237 30 13 (8-20) 6 (4-8) 24 (11-36) 11 (4-18) 20 (12-36) 14 (2-25) 28 (12-47) 13 (6-24) FP, 250 BDP, 1500 BUD, 800 BUD, 300 BUD, -800 BDP, 300 FP, 200 FP, - 200 MDI NEB MDI MDI MDI MDI MDI MDI 26 2 12 6 26 6 12 26 S+LF S S S S S + LF S S

No effect
Maayan86 v. Bever90 Stick 95 Barrueto 02 Hofhuis 05 9 23 38 31 62 6 (4-8) 10 (3-17) 12 (5-18) 16 (14-18) 11 (7-20) BDP, 1500 BUD, 1000 BDP,400 BDP,400 FP, 200
NEB NEB

2 4 8 8 13

LF S S + LF S S + LF

MDI MDI MDI

RCT on ICS in wheezing < 4 yr

n Age (months) Drug, Daily dose Device wks

Endpoints Symptoms or LF

Effect
Teper 05 Maayan86 Bisgaard90 Noble 92 Connett 93 Kraemer97 Bisgaard99 Teper 04 26 9 77 15 40 29 237 30 13 (8-20) 6 (4-8) 24 (11-36) 11 (4-18) 20 (12-36) 14 (2-25) 28 (12-47) 13 (6-24) FP, 250 BDP, 1500 BUD, 800 BUD, 300 BUD, -800 BDP, 300 FP, 200 FP, - 200 MDI NEB MDI MDI MDI MDI MDI MDI 26 2 12 6 26 6 12 26 S+LF S S S S S + LF S S

No effect
Maayan86 v. Bever90 Stick 95 Barrueto 02 Hofhuis 05 9 23 38 31 62 6 (4-8) 10 (3-17) 12 (5-18) 16 (14-18) 11 (7-20) BDP, 1500 BUD, 1000 BDP,400 BDP,400 FP, 200
NEB NEB

2 4 8 8 13

LF S S + LF S S + LF

MDI MDI MDI

ICS in wheezing < 4 yrs

n=26, age 7.5 20 months Min. 3 wheezing episodes with BDR Fam history of asthma, allergic rhintis and/or eczema Decreased ILFT (Z-score VmaxFRC < -1 )

FP 2 dd 125 ug by MDI and spacer for 6 months

Diary cards

Teper at al. AJRCCM 2005

ICS in wheezing < 4 yrs

-0.74 0.6 vs 0.44 1 Teper. AJRCCM 2005.

-0.79 0.3 vs -0.78 1.4

ICS in wheezing < 4 yrs

n=62, 424 months min. 3 wheezing episodes, or 1 period of prolonged persistent wheezing > 2 mo RCT, PLAC or FP 2 dd 100ug for 3 months

ILFT at start and end of study

Diary cards for symptom scores and beta-2 agonist use

Hofhuis et al. AJRCCM 2005.

ICS in wheezing < 4 yrs

Change in VmaxFRC not different
Change in symptoms not different Similar results if only atopic children analysed

Hofhuis et al. AJRCCM 2005.

ICS in wheezing < 4 yrs

Effect of ICS more pronounced in children > 2 years with high risk for asthma Limited evidence that ICS reduce inflammation (FENO) No clinical benefits from systemic or ICS during the acute-phase of viral wheeze in previously healthy infants Response to ICS in children with moderate-severe persistent wheeze with viral-induced symptoms (less exacerbations)

ICS in wheezing < 4 yrs

Risk of side effects ICS on developing lung
Early intervention to prevent remodeling? Selection of responsive children?

Asthma in preschool children

Epidemiology
Why infants wheeze Why we should make a diagnosis

How to make a diagnosis

Treatment Prevention

Prevention of asthma with ICS?

3 double blind, placebo controlled RCT:

Guilbert et al. NEJM 2006; 354: 1985-97. Bisgaard et al. NEJM 2006; 354: 1998-2005. Murray et al. Lancet 2006; 368: 754-62.

Prevention of asthma by ICS

Study design
fluticasone 285, high risk age 2 3 yrs 4 wheezing episodes

placebo

2 yrs treatment Guilbert et al. NEJM 2006.

1 yr observation

Prevention of asthma by ICS

p = 0.006 p = 0.78

Proportion of episode-free days

treatment

observation
ns

Guilbert et al. NEJM 2006.

Prevention of asthma by ICS

budesonide as needed
294 infants with an asthmatic mother
Starting at 1st episode Start at day 3 for 2 wks Clinic visit < 24 h Repeat every episode

placebo as needed

Persistent wheezing?

age 3 yrs

Bisgaard et al. NEJM 2006.

Prevention of asthma by ICS

% persistent wheezing

p = 0.41
Budesonide 24%

Placebo 21%

Days after randomization

Bisgaard et al. NEJM 2006.

Prevention of asthma by ICS

n = 206, parental atopy, median age 1.7 yrs

start at 2nd wheezing episode > 24 h or 1st prolonged episode (doctor diagnosed)
fluticasone 2 x 100 g vs placebo dose reduction/ open label FP if appropriate follow up till age 5 yrs: sRaw, FEV1, AHR
Murray et al. Lancet 2006.

Prevention of asthma by ICS

No differences at age 5 in: Current wheeze Doctor diagnosed asthma Use of asthma medication

Need for open label use of fluticasone

Lung function Airway reactivity

Murray et al. Lancet 2006.

Prevention of asthma by ICS?

Prevention no

Control
Prevention Control

yes
no no

Prevention Control

no yes?

Prevention of asthma?
Probiotics
Smoking Breast feeding

Conclusions
Wheezing in preschool children is very common and has a benign course in the majority of children
Anatomical, physiological and immunological considerations make infants prone to wheezing Making a diagnosis is important to select children likely to benefit from ICS and estimate prognosis

Conclusions
A high predictive index is most useful to diagnose asthma in preschool children
In high risk children > 2 yrs of age ICS are most likely to be beneficial Primary prevention of asthma is not possible till now

LTRA treatment
In high risk children with elevated NO, positive respons on lung function and eNO.

Montelukast in wheezing < 4 yrs

2-5 yr old children Intermittent asthmatic symptoms due to viral infections DB RCT montelukast (n = 278) or placebo (n = 271) for 12 months

Montelukast
reduced exacerbation rate by 32% Delayed time to first exacerbation with 2 months

Bisgaard et al. AJRCCM 2005

 However, Small decrease in exacerbations No change in prednisone courses 30% evidence of atopy

 Wheezing children (median 15 mo) higher total cell counts (macrophages, lymphocytes, neutrophils) compared to controls. Eosinophils not predominant.
(Krawiec et al. AJRCCM 2001)

Higher eosinophils in atopic asthmatic children compared to atopic nonasthmatic and viral wheezers.
(Stevenson, Clin Exp Allergy 1997)

Treatment - ICS
Persistent wheezing: ICS effective
Gleeson & Price, (2-6 jr, n=39) BMJ 1988; Bisgaard (1-3 jr, n=77), Lancet 1990; Roorda (1-4 jr, n=169), J Allergy Clin Immunol 2001

NB:

More severe symptoms, age> 2 yr typical asthma symptoms

episodic viral wheeze: ICS not effective

Doull, BMJ 1997, 7-9 yrs, n=104, 6 mo 2 x 200 g beclomethason PDI Wilson, Arch Dis Child 1995, 1-6 yrs, n=41, 4 mo 2 x 200 g budesonide via plastic spacer

? Dosis high enough ? Administration long enough?

ICS in wheezing < 4 yrs

n = 31, mean 12.7 months Recurrent wheeze and parental atopy Elevated FENO > 10 ppb

FP or placebo for 4 weeks

Moeller et al. Pediatr Pulmonol 2004.

ICS in wheezing < 4 yrs

Moeller et al. Pediatr Pulmonol 2004.

Smoking during pregnancy

Inhibits normal development and growth of lungs and airways
Long lasting effect on development of airways Lower lung function in infants Reduction in alveolar attachments Associated with airway symptoms in preschool children

ETS exposure after birth

>50% of all children OR wheezing 1.3 - 1.4 OR asthma 1.4 1.6 OR RTI 1.6-1.9 Strong dose-effect relation No strategies have been proven to reduce exposure
Dutch Health Council 2004

Exhaled nitric oxide in preschool wheeze

Meyts et al. Eur J Pediatr 2003.

Probiotics and atopy

n=461 probiotics, n=464 placebo. Starting before delivery, till 6 months of age. High risk infants. no effect on all allergic diseases at age 2 yrs

reduction (atopic) eczema OR 0.74 (95% CI 0.55-0.98, p=0.035) and OR 0.66 (95% CI 0.46-0.95, p = .025)
(Kukkonen et al. JACI 2007;119:192-8)

Reduction atopic eczema at age 4

(Kalliomaki et al, Lancet 2003 en 2005)

Prevention of asthma: breastfeeding

Meta-analysis 12 prospective studies > 3 mo breast-feeding vs asthma diagnosis or wheeze > 1 yr at the age of 3-7 yr

OR 0.52 if positive family history OR 0.7 total

Gdalevich, JPed 2001